Metabolic rewiring controlled by HIF-1α tunes IgA-producing B-cell differentiation and intestinal inflammation
Xianyi Meng, Sahar Asadi-Asadabad, Shan Cao, Rui Song, Zhen Lin, Mohammed M. Safhi, Yi Qin, Estelle Tcheumi Tactoum, Verena Taudte, Arif B. Ekici, Dirk Mielenz, Stefan Wirtz, Georg Schett, Aline Bözec
Abstract
Germinal centers where B cells undergo clonal expansion and antibody affinity maturation are hypoxic microenvironments. However, the function of hypoxia-inducible factor (HIF)-1α in immunoglobulin production remains incompletely characterized. Here, we demonstrated that B cells lacking HIF-1α exhibited significantly lower glycolytic metabolism and impaired IgA production. Loss of HIF-1α in B cells affects IgA-producing B-cell differentiation and exacerbates dextran sodium sulfate (DSS)-induced colitis. Conversely, promoting HIF-1α stabilization via a PHD inhibitor roxadustat enhances IgA class switching and alleviates intestinal inflammation. Mechanistically, HIF-1α facilitates IgA class switching through acetyl-coenzyme A (acetyl-CoA) accumulation, which is essential for histone H3K27 acetylation at the Sα region. Consequently, supplementation with acetyl-CoA improved defective IgA production in Hif1a-deficient B cells and limited experimental colitis. Collectively, these findings highlight the critical importance of HIF-1α in IgA class switching and the potential for targeting the HIF-1α-dependent metabolic‒epigenetic axis to treat inflammatory bowel diseases and other inflammatory disorders.